Crystallization method is a method of precipitating crystals by utilizing crystallization phenomenon in a non-equilibrium state, where supersaturation is a driving power. For crystallization of a pharmaceutical compound, an Anti-solvent (poor solvent) Crystallization method capable of operating at ambient temperature is often used to avoid heat denaturation of the object compound. The poor solvent crystallization method is a method including dissolving a compound, which is insoluble in water and the like, in a good solvent, and mixing the compound solution with another solvent (water etc.) to allow for precipitation of crystals by creating a supersaturation state of the solution. The crystals obtained by this method have high purity, and the yield of the solute is determined by the kind and the amount added of the poor solvent. Therefore, crystals can be obtained at a high yield rate from a solution having a high solubility, and the method is drawing attention as a means for improving the yield of a pharmaceutical compound. At present, there are many products using the crystallization method (non-patent document 1). It is also possible to use the crystallization method for amorphous forms, which confers crystallinity by heating/cooling or pressurizing/reducing pressure and the like.
However, since the technique for highly controlling the crystal quality is immature, microparticulation, achievement of uniform particle size distribution and the like are the problems. When the pharmaceutical compound is poorly water-soluble and has a large particle size, the dispersibility during formulation of a liquid medicine becomes poor, and addition of an additive to the solvent is required. When an injection is prepared, a large-sized injection needle is required, which problematically increases the burden on patients. Therefore, respective researchers use a high-pressure crystallization apparatus (PureNano etc.), a high-pressure homogenizer, a homogenizer, Starburst and the like, Wet-Milling apparatus and the like for microparticulation and improvement of particle size distribution (non-patent document 2). They are defective in that the former (high-pressure crystallization apparatus, high-pressure homogenizer, homogenizer, Starburst etc.) requires high energy, and the latter (Wet-Milling apparatus) generally requires a long operation time, shows a decreased yield, has difficulty in large-scale operation and the like. The development of a crystallization method capable of preparing fine crystals having a uniform particle size and permitting easy microparticulation and homogenization operation after precipitation has been desired.
Patent document 1 describes a method of producing nanosized particles and hollow particles by, in poor solvent crystallization, generating air bubbles in a poor solvent, mixing the solvent with an organic pigment solution, and precipitating fine particles of the organic pigment on the surface of the air bubbles. As a means for generating the air bubbles, a swirling flow-type micro-bubble generator and an ultrasonication generator that generates micro cavities are described. However, since the particle size tends to grow as the degree of crystallinity of the organic pigment increases, a microparticulation method including crushing air bubbles by an ultrasonic generator to disrupt and disperse the particles coagulated on the surface of the air bubbles has been employed. In addition, application to poorly water-soluble pharmaceutical compounds is not suggested at all.